Gut-Brain Axis Modulation by Fermented Food-Derived Metabolites

Abstract

Fermented foods have moved from a niche interest within nutritional microbiology to a subject of active
neuroscience research over the past decade, driven by accumulating evidence that microbial metabolites
generated during fermentation, and further transformed by the resident gut microbiota after ingestion, can
influence central nervous system function through several distinct, only partially overlapping signalling routes. This
review synthesises evidence from mechanistic, animal and human intervention studies on four classes of
fermented-food-derived metabolite with reasonably well-characterised gut-brain signalling activity: short-chain fatty
acids (principally butyrate, propionate and acetate) generated by microbial fermentation of dietary fibre and
residual carbohydrate; biogenic amines and their precursors, including gamma-aminobutyric acid (GABA)
produced by lactic acid bacteria during fermentation of dairy, soy and vegetable substrates; bioactive peptides
released by microbial proteolysis during fermentation of milk and legume proteins; and bacterial and fungal
exopolysaccharides and cell-wall components capable of modulating intestinal immune signalling. We evaluate
the evidence for four candidate signalling routes linking these metabolites to central nervous system outcomes:
direct vagal afferent stimulation via enteroendocrine cell signalling, systemic absorption and blood-brain barrier
crossing, indirect modulation of circulating immune and inflammatory mediators, and
hypothalamic-pituitary-adrenal axis modulation via cortisol and related signalling. Randomised controlled trials of
fermented food consumption on mood, cognition or stress-reactivity outcomes remain comparatively few,
heterogeneous in fermented food type and dose, and generally underpowered relative to the effect sizes they
report, a pattern that recurs across the human intervention literature we reviewed. We conclude that mechanistic
and preclinical evidence for gut-brain signalling by fermented-food metabolites is substantial and increasingly well
characterised at the level of individual metabolite classes, but that clinical evidence for behaviourally or
psychologically meaningful effects of habitual fermented food consumption in humans remains preliminary, and
we set out a specific research agenda, centred on standardised dosing, metabolite quantification, and adequately
powered trial design, that we think is needed to close that gap credibly.